At the molecular level, cellular responses to ionizing radiation are determined by differential gene expression. Pathways of signal transduction cell cycle regulation, repair processes and programmed cell deathh (apoptosis), are all included in the events underlying radiation sensitivity or resistance. In this program project, our overall hypothesis that key proteins functioning in signal transduction pathways are associated with tumor cellular radiation sensitivity or resistance. We will investigate several of these proteins to determine mechanisms of action, as they relate to cellular responses to ionizing radiation. We have organized our investigations in seven projects and two cores. We will study the roles of NF-khib/ikhibalpha radiation sensitivity and programmed cell death in projects #1 and 2, respectively. Programmed cell death and poly (ADP- ribose) polymerase mechanisms will be investigated in projects #3 and 4. Radiation sensitivity of thymidine kinase deficient cells will be studied i project #5. Preclinical evaluation of antisense oligonucleotide to c-raf-1 ll be performed in human tumor xenograft model system, extending our previous laboratory observations with antisense RNA to this oncogene. Finally, a prospective clinical trial will be performed to determine the ro of ATM heterozygosity in breast cancer and acute radiation reactions. These projects run the gamut of investigations from basic science to clinical translation, centering on molecular mechanisms underlying cellular radiation responses. Data from these projects will enhance our understanding of radiation sensitivity, apoptosis, and may provide the basis for a clinical test to diagnose ATM heterozygotes.